1Radiology,
University of Pennsylvania, Philadelphia, PA, United States; 2Pharmacology,
University of Pennsylvania, Philadelphia, PA, United States; 3Radiation
Oncology, Thomas Jefferson University, Philadelphia, PA, United States

Synopsis: The inverted pH gradient between the inside
and outside of cells that is observed in tumors presents both obstacles to
and opportunities for cancer therapy. As a consequence of their high levels
of aerobic glycolysis, DB-1 melanoma xenografts exhibit a selective decrease
in their intracellular pH by ~0.6 units following treatment with the
lonidamine (LND), which inhibits the export of lactic acid from the tumor
cell via the monocarboxylic acid transporter (MCT). In addition, LND
decreases the bioenergetics state of the tumor by inhibiting transport of
pyruvate into mitochondria via the mitochondrial pyruvate carrier (MPC).
Under these conditions, doxorubicin accumulates in the tumor as a result of
protonation of its amino group (i.e., cation trapping), which produces a
pronounced enhancement of the antineoplastic activity of this anthracycline.
Treatment of DB1 melanomas with doxorubicin following tumor acidification
with LND produced long-term (>50 day) growth delays in four out of five
melanoma xenografts demonstrating the potential clinical utility of combining
LND with doxorubicin in the treatment of melanoma and other human cancers.